Long range goals represented by this proposal include obtaining mechanistic knowledge of interferon-based therapies in the context of bladder transitional cell carcinoma treatment ongoing at M.D. Anderson Cancer Center. Bladder cancer is the sixth leading cause of cancer in the United States, excluding skin, and continues to provide a challenge regarding treatment due to its high recurrence rate. The hypothesis is that interferons exhibit antitumoral effects via death receptor mechanisms. Based on this, the specific aims for this proposal are as follows: (1) define defects in the interferon signaling pathway contributing to interferon resistance, (2) characterize molecular defects in death receptor pathways contributing to death receptor resistance, and (3) determine death receptor involvement in tumor progression and responses to interferon-based therapy in vivo.